Quantum Biochemistry Description of the Human Dopamine D3 Receptor in Complex with the Selective Antagonist Eticlopride

Abstract

In the quest to improve the treatment of Parkinson´s disease and Schizophrenia, one of the proposed strategies has been the development of subtype selective ligands targeting D2 and D3 dopamine receptors. An essential advance for this type of strategy was the recent crystallographic elucidation of the human dopamine D3 receptor structure in complex with the antagonist eticlopride, revealing important features of the ligand-binding pocket. Taking this data into account, we have performed a quantum biochemistry investigation of the eticlopride binding to D3 in order to understand the implications and the individual contribution of amino acid residues at the binding pocket. The contribution of the residues were evaluated using the molecular fractionation with conjugate caps approach and binding energies calculated within the framework of the density functional theory using both the local density and generalized gradient approximations. The simulations show that the total interaction energy of eticlopride bound to D3 stabilizes only for a pocket radius of at least 8.0A. The strongest estimated drug-residue interaction energy was observed for Asp110 followed, among others, by Phe345, Phe346, Ile183, Val107, Tyr373, Val189, Trp342, Cys114 and Val82 hydrogen and van der Waals bonds, the later being a repelling residue which was not considered to be important in the original crystallographic data analysis. Our results highlight the key amino acid residues involved in the binding of antipsychotics to D3R and collaborate to a potential further analysis with regard to the binding of different antagonists in members of the dopamine receptor family.